ES2371147T3 - DERIVATIVES OF AZABICICLO [3.1.0] USEFUL HEXANE AS MODULATORS OF D3 DOPAMINE RECEIVERS. - Google Patents

Abstract

3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4- (trifluoromethyl) phenyl] -3 -azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, corresponding to a compound of formula (I): (R 1) p wherein - G is phenyl and (R1) p is 4-trifluoromethyl; - R2 is hydrogen; - R3 is methyl; - R4 is 4-pyridazinyl G N (CHR 2) (CH 2) 2.

Description

Azabicyclo [3.1.0] hexane derivatives useful as modulators of D3 dopamine receptors.

The present invention relates to new compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of D3 dopamine receptors.

WO 2002/40471 (SmithKline Beecham) describes certain benzazepine compounds that have activity in

the D3 dopamine receptor.

WO 00/42037 (BASF AG) refers to triazole compounds of formula (I), wherein R1, R2 and

B have the meanings given in the description.

NN

(I)

AB R1

The compounds provided in the invention have high affinity for the dopamine D3 receptor and, therefore, can be used for the treatment of diseases that respond to the influence of dopamine D3 ligands.

WO 03/035622 (PFIZER PRODUCTS INC.) Describes compounds of formula (I) in which X, Q,

15 n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined. The compounds of formula (I) have activity as opioid antagonists, in particular against substance abuse.

(CH2) n

A new class of compounds having affinity towards dopamine receptors, in particular the D3 dopamine receptor, has been discovered. These compounds have potential in the treatment of conditions in which modulation of the D3 receptor, especially antagonism / inhibition, is beneficial, e.g. ex. to treat drug dependence or as antipsychotic agents.

WO 01/098267 (PFIZER LIMITED) describes compounds of formula (I),

R5 (I)

R7

(O) q

where the substituents are as defined herein, and the pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof, which are pharmaceutically and veterinarily useful. They are probably useful in the treatment of diseases or conditions modulated by recipients of

5 opiates, for example, addiction to tobacco and alcohol, among others.

WO 2004/014881 (ASTRA ZENECA AB) describes new compounds of formula (I)

(R3) n (R1) m X1 M2 X4

(R4) m (I) M1

X3 (R2) n X2

a process for its preparation and new prepared intermediates, pharmaceutical formulations containing said compounds and the use of said compounds in therapy.

10 A new class of compounds having affinity towards dopamine receptors, in particular the D3 dopamine receptor, has been discovered. These compounds have potential in the treatment of conditions in which modulation, especially antagonism / inhibition, of the D3 receptor is beneficial, e.g. ex. to treat drug addictions or as antipsychotic agents.

The present invention provides a compound of the formula (I):

3- (3 - {[4-Methyl-5- (4- (pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane

or a pharmaceutically acceptable salt thereof,

N N N (CHR2) (CH2) 2 S

(I) N

R4 (R1) p

R3

in which

• G is phenyl and (R1) p is 4-trifluoromethyl; 20 • R2 is hydrogen;

•

R3 is methyl;

•

R4 is 4-pyridazinyl

Due to the presence of the cyclopropane condensed compounds, it is believed that the compounds of formula (I) have a "cis" arrangement of the substituents (the two groups attached to the bicyclic ring system 25 are on the same side of this system of bicyclic rings).

In another embodiment of the present invention, compounds of the formula (I) ’are provided which correspond to the compounds of the formula (I) having disposition" cis "represented by the links highlighted in bold

N N

N (CHR2) (CH2) 2 S

(I) 'N R4 (R1) p

R3

5 wherein G, p, R1, R2, R3, R4 and R5 are defined as defined above for the compounds of formula (I).

It will be appreciated that the compounds of formula (I) ’possess at least two chiral centers, namely at position 1 and 5 in the 3-azabicyclo [3.1.0] hexane portion of the molecule. Due to the fixed cis arrangement, the compounds may exist in two stereoisomers that are enantiomers with respect to the chiral centers of the cyclopropane. It will also be appreciated that, as with most biologically active molecules, the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention include all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, which include, but are not limited to, racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures.

15 described herein.

In the compounds of formula (I) ’there are at least two chiral centers, which are located in the cyclopropane portion, as shown below (the bold highlighting of the links indicates the“ cis ”configuration);

N H N N (CHR2) (CH2) 2 S

(I) 'N

*

*

R4 (R1) p 1

R3 Resolution

N

H N (CHR2) (CH2) 2 S N

(IA) N

*

* 1 R4

(R1) p

R3

configuration (1S, 5R)

In a further embodiment of the present invention, compounds of formula (IA) corresponding to the stereochemical isomers of compounds of formula (I) ', enriched in the configuration (1S, 5R) are provided

N

H

5 N

N (CHR2) (CH2) 2 S

(IA)

1 N

(R1) p

R4

R3

wherein G, p, R1, R2, R3, R4, and R5 are defined as before for the compounds of formula (I) 'or a pharmaceutically acceptable salt thereof.

In the context of the present invention, it is intended that the stereochemical isomers enriched in the

5 configuration (1S, 5R) or (1R, 5R) of formula (IA) correspond in one embodiment to at least 90% e.e. In another embodiment, the isomers correspond to at least 95% e.e. In another embodiment, the isomers correspond to at least 99% e.e.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts 10 and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications due to their greater aqueous solubility with respect to the original compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably, the physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids, such as hydrochloric, hydrobromic, iohydric, phosphoric, metaphosphoric, nitric and sulfuric acids and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, canforsulfuric, isotionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, ascorbic, ascorbic acid , salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinyl, alginic, galacturonic and arylsulfonic, for example, benzenesulfonic acid and p-toluenesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and salts formed internally. Salts having an anion or cation that is not physiologically acceptable are within the scope of the invention as intermediates useful for the preparation of physiologically salts.

Acceptable and / or for use in non-therapeutic situations, for example, in vitro.

In one embodiment, a compound of formula (IB) or a salt thereof is provided, wherein R1, p, R3 and R4 are as defined for formula (I):

N

N N (CH2) 3 S

(IB) N

R4 (R1) p

R3

The strategy for determining the absolute configuration of the compounds of the present invention comprises, as a first step, the preparation of the chiral intermediate, (1S, 5R) -1- [4- (trifluoromethyl) phenyl] 3-azabicyclo [3.1 .0] hexane,

(preparation 18), using (S) - (+) acetylmandleic acid as the resolution agent.

The absolute configuration of a series of compounds similar to this chiral intermediate is known in the literature, see J. Med. Chem. 1981, 24 (5), 481-90. For some compounds disclosed in the reference the absolute configuration was tested by single crystal X-ray analysis.

Cl

5 Among them, 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was described.

The absolute configuration of the optical isomers of the compounds of the present invention was assigned through the use of comparative VCD analysis (vibrational circular dichroism) and OR (optical rotation).

The configuration of (1S, 5R) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was assigned by comparing its experimental spectrum by VCD and the specific rotation observed with the calculated derived data

10 initially for (1S, 5R) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane (see Preparation 48) as a reference sample.

The assignment of the absolute configuration of the title compound was confirmed by a single crystal X-ray structure obtained from stal of (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1. 0] hexane, acid salt (S) - (+) - mandelic. Both analysis based on the known configuration of acid (S) - (+)

Mandelic as based on anomalous dispersion effects confirmed the assignment of the title compound as (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane.

For the compounds that underwent a detailed analysis (VCD; OR included in the experimental details) a common trend was recognized between the absolute configuration of the rest of 3azabicyclo [3.1.0] hexane and the binding activity measured to the dopamine D3 receptor for each pair of

20 enantiomers For the rest of the compounds of the present invention, in which the stereoisomers were studied separately, the absolute configuration was assigned based on a reasonable assumption by one skilled in the art, that is, the absolute configuration was then assigned based on the binding activity measured to the dopamine D3 receptor for both enantiomers, and comparison with the data of the compounds that were subjected to a detailed analysis.

25 The chiral molecules show vibrational circular dichroism (VCD). Vibrational circular dichroism (VCD) is the differential interaction of a chiral molecule with infrared radiation circularly polarized left and right during vibrational excitation.

The VCD spectrum of a chiral molecule depends on its three-dimensional structure. More importantly, the VCD spectrum of a chiral molecule is a sensitive function of its absolute configuration and, in the case of flexible molecules, of its conformation. In principle, therefore, the VCD allows the determination of the structure of a chiral molecule. VCD spectra were measured for the first time in the 1970s. Subsequently, VCD instrumentation has developed greatly in spectral range and sensitivity. Currently, the VCD spectra of liquids and solutions can be measured over almost the entire fundamental infrared (IR) spectral range (v650 cm-1) with high sensitivity to

35 acceptable resolution (1–5 cm-1) using both VCD instrumentation of both dispersion and Fourier Transform (FT). Very recently, VCD FT instrumentation is available on the market, which has greatly improved the accessibility of VCD spectra.

Currently, the use of VCD has been tested as a safe method for determining the absolute configuration of chiral molecules (see, for example, Shah RD, et al., Curr Opin Drug Disc Dev 40 2001; 4: 764-774; Freedman TB, et al., Helv. Chim. Acta 2,002; 85: 1,160-1,165; Dyatkin AB, et al. Chirality 2,002; 14: 215-219; Solladie-Cavallo A, Balaz Met al., Tetrahedron Assym 2,001; 12: 2,605–2,611; Nafie LA, et al. Circular dichroism, principles and applications, 2nd ed. New York: John Wiley &Sons; 2,000, p. 97– 131; Nafie LA, et al. In: Yan B, Gremlish HU, eds. Infrared and Raman spectroscopy of biological materials. New York: Marcel Dekker; 2,001, p. 15–54; Polavarapu PL, et al., J Anal Chem 2,000; 366: 45 727–734; Stephens PJ, et al., Chirality 2,000; 12: 172-179; Solladie´-Cavallo A, et al., Eur J Org Chem

2,002: 1,788–1,796).

The method involves comparing the IR and VCD spectra observed with spectral calculations for a specific configuration and provides information on the absolute configuration and on the conformation of the solution.

Given an experimental spectrum of a chiral molecule whose absolute configuration and / or conformation are unknown and must be determined, the general procedure is as follows: 1) all possible structures are defined; 2) the spectra of these structures are predicted and 3) the predicted spectra are compared with the experimental spectrum. The correct structure will give a spectrum according to the experiment; Incorrect structures will give spectra at odds with the experiment.

VCD spectra are always measured simultaneously with vibrational non-polarized absorption spectra ("infrared (IR) spectra") and the two vibrational spectra together provide more information than the VCD spectrum alone. In addition, vibrational non-polarized absorption spectra are automatically predicted simultaneously with the VCD spectra.

For ab initio assignments, the non-polarized VCD and IR spectra were calculated using the Gaussian 98 computer application.

When chiral organic molecules (or, if natural products are isolated) are synthesized, their optical rotations are routinely measured at a frequency or a small number of discrete frequencies in the near visible ultraviolet spectral region. Most frequently, the specific rotation at a frequency, that of the sodium D line, [a] D is measured. The frequencies used are below the electronic absorption threshold, that is, they are in the spectral region "transparent". Optical rotation is a reflection of the enantiomeric excess (ee) of the sample and the absolute configuration (CA) of the predominant enantiomer.

When the optical rotation is available at a given frequency for 100% ee, the optical rotation measured at the same frequency makes it possible to determine the ee of the sample.

The determination of the ee is the predominant application of the optical rotations of the transparent spectral region, with discrete frequency. In principle, the CA of the predominant enantiomer, if unknown, can also be determined. However, the determination of the CA from the optical rotation requires an algorithm that reliably predicts the optical rotations of known AC molecules and a series of methodologies have been proposed to predict the optical rotations of the transparent spectral region frequently. discreet (Eliel EL, Wilen SH. Stereochemistry of organic compounds. New York: John Wiley &Sons; 1994. Chapter 13).

Very recently, the developments at the beginning of the Functional Theory of Density (TFD) have radically improved the accuracy of the calculation of optical rotation. As a result, for the first time it has been possible to routinely obtain the CAs of optical rotations.

For initial OR assignments, the Dalton Quantum Chemistry Program was used.

Other embodiments of the present invention are compounds of formula (IB) ’which correspond to the stereochemical isomers of compounds of formula (IB) as defined above enriched in the configuration (1S, 5R).

In one embodiment, a stereochemical isomer enriched in the configuration (1S, 5R) of the formula (IB) 'or a salt thereof is provided, wherein R1, p, R3 and R4 are as defined for the formula (I ):

N

N N (CH2) 3 S

H

(IB) 'N

R4 (R1) p R3

Certain compounds of the invention may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I), using conventional methods.

Those skilled in the art of organic chemistry will appreciate that many organic compounds may complex with solvents in which they are reacted or in which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate."

Solvates of the compound of the invention are within the scope of the invention. The compounds of formula (I) can be easily isolated associated with solvent molecules by crystallization or evaporation of an appropriate solvent, to provide the corresponding solvates.

As used herein, the term "prodrug" refers to a compound that is converted, inside the body, for example, by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described by T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ”, Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each incorporated herein by reference.

Prodrugs are any covalently bound vehicle that releases a compound of structure (I) in vivo when said prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups such that the modification is cleaved, by routine manipulation or in vivo, producing the parent compound. Prodrugs include, for example, compounds of this invention in which the hydroxy, amine or sulfhydryl groups are attached to any group that, when administered to a patient, is cleaved to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, format and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). In addition, in the case of a carboxylic acid (-COOH), esters, such as methyl esters, ethyl esters and the like can be used. The esters can be active by themselves and / or can be hydrolyzed under conditions in vivo in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily degrade in the human body to leave the acid of origin or its salt.

In addition, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.

Those skilled in the art will appreciate that in the preparation of the compound of the invention or one of its solvates, it may be necessary and / or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Protective groups suitable for use according to the present invention are well known to those skilled in the art and can be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (eg formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (eg benzyloxycarbonyl (Cbz) and substituted Cbz), type protecting groups aliphatic urethane (eg 9-fluorenylmethoxycarbonyl (Fmoc), t-butoxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (eg benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include, for example, alkylsilyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers, such as tetrahydropyranyl or tert-butyl; or esters, such as acetate.

When a specific enantiomer of a compound of general formula (I) is required, it can be obtained, for example, by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Therefore, the required enantiomer can be obtained from the racemic compound of formula (I) by the use of a chiral HPLC method.

The present invention also includes compounds labeled with isotopes, which are identical to those indicated in formula (I) and following, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass Atomic or mass number that is normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C , 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and 125I.

The compounds of the present invention and the pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H, 14C are incorporated, are useful in tissue distribution assays of drugs and / or substrates. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detection. Isotopes 11C and 18F are particularly useful in PET (positron emission tomography), and isotope 125I is particularly useful in SPECT (single photon emission computed tomography), all useful in brain imaging. In addition, substitution with heavier isotopes, such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, a greater half-life in vivo or lower dosage requirements and, therefore, may be preferred in Some circumstances The isotope-labeled compounds of formula I and following of this invention can be prepared, in general, by performing the procedures described in the Schemes and / or in the Examples shown below, substituting an unlabeled isotope reagent for a reagent. easily acquired isotope labeling.

Certain groups / substituents included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers, tautomers and mixtures thereof. Some of the substituted heteroaromatic groups included in the compounds of formula (I) may exist in one or more tautomeric forms. The present invention includes within its scope, all these tautomeric forms, including mixtures.

In one embodiment of the present invention, compounds with a molecular weight of 800 or less are provided. In another embodiment, compounds having a molecular weight of 600 or less are provided. In general, and not limited to the same, such compounds may have greater oral bioavailability and sometimes greater solubility and / or brain penetration. The molecular weight herein refers to that of the compound as a free base without solvating, excluding any contribution to the molecular weight of the addition salts, solvent molecules (eg water), molecular parts of the prodrug cleaved in vivo, etc.

In general, it should be construed that the compounds or salts of the invention exclude compounds (if any) that are so chemically unstable, either by themselves or in water, that they are clearly unsuitable for pharmaceutical use by all routes of administration, whether oral, parenteral or in any other way. Such compounds are known to the skilled chemist. Prodrugs or compounds that are stable ex vivo and that are convertible in the body of mammals (eg, the human being) into inventive compounds are however included.

Exemplary compounds of the present invention include:

• (1S, 5R) -3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4- (trifluoromethyl) phenyl] -3azabicyclo [3.1.0] hexane;

and its pharmaceutically acceptable salts.

The present invention also provides a process for preparing a compound of formula (I) or a salt thereof, as defined above.

In one aspect of the present invention, a synthesis process is provided for the preparation of compounds of the formula (II). This process includes the following stages:

OR

NH NH2 (R1) p

OR

(R1) p

(a ') (VII)

(VIII) OO

NH NH (R1) p O O

(R1) p (b ')

(VIII) (IX) OR

NH

NH O (R1) p (R1) p (c ') (II) (IX)

where:

step (a ') means diazotization of an aniline (VII) followed by reaction with maleimide providing 3-arylmaleimide (VIII);

5 step (b ') means cyclopropagation of (VIII) providing the bicyclic imide (IX);

step (c ') means reduction of the imide (IX) by providing compounds of the formula (II).

Step (a ’) can be performed using conventional methods for the Meerwein reaction (for example, J. Am. Chem. Soc. 1955, 77, 2.313 describes the formation of arylmaleimides using this approach). Alternatively, in many cases, this stage is performed properly by applying a procedure in

10 that to a mixture of maleimide, an appropriate copper (II) salt such as anhydrous CuCl2 and a suitable organonitrite, such as tert-butyl nitrite, in a compatible solvent, such as acetonitrile, is slowly added a solution of a compound of the formula (VII). This is followed by a period of time during which it is allowed to react as appropriate and an appropriate treatment. Preparation 37 exemplifies this procedure.

Step (b ') consists of the slow addition of a solution of purified compound of the formula (VIII) or mixtures thereof, which contains a compound of the formula (VIII), dissolved in a suitable solvent such as dimethylsulfoxide, to a dissolution of trimethylsulfoxonium iodide in a suitable solvent such as dimethylsulfoxide and a suitable base, such as sodium hydride. This is followed by a period of time during which it is allowed to react as appropriate and an appropriate treatment. Preparation 37

20 exemplifies this procedure.

Step (c ') can be carried out using a suitable reducing agent in a compatible solvent, such as borane in tetrahydrofuran or Red-Al® in toluene at an appropriate temperature, such as at 65 ° C in the case of borane as a reducing agent. This is followed by proper treatment. Preparation 38 exemplifies this procedure.

In another aspect of the present invention an alternative synthetic process is provided for the preparation of the compounds of formula (II), or in general of formula (XIII). This process includes the following stages:

N PG

Y

OR

R14

(R1) p

(R1) p

BO

R14

N

PG +

(to'')

(X) (XI) (XII)

N PG H

NH

(R1) p

(R1) p

(b '')

(XII) (XIII)

where:

R1, p and G are as defined for formula (I), R14O is a suitable alkoxy group, PG is an appropriate protecting group and Y can be halogen such as bromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxy, and It comprises the following stages:

step (a '') means coupling reaction of a (2,5-dihydro-1H-pyrrol-3-yl) boronate (X) with the halo or aromatic sulfonyloxy derivative (XI);

stage (b ’’) means cyclopropagation of (XII) followed, if appropriate, of deprotection by providing the bicyclic amine (XIII).

Step (a '') can be performed using conventional methods for Suzuki coupling, for example using tetrakis (triphenylphosphine) palladium (0) as a source of catalytic palladium (0) in the presence of cesium fluoride, in an appropriate solvent such as tetrahydrofuran at a suitable temperature. (R14O) 2B may suitably be 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and benzyl PG, which represents a compound of structure (X) as reported in Synlett 2.002 , 5, 829-831. Preparation 50 exemplifies

15 this procedure.

Step (b '') consists of a cyclopropane reaction carried out, for example, using the reagent generated from trimethylsulfoxonium iodide and a suitable base such as sodium hydride, in a compatible solvent, for example dimethyl sulfoxide. Preparation 52 exemplifies this procedure. A deprotection reaction is then carried out as shown in Preparation 54.

The compounds of formula (I) wherein R1, R2, R3, R4, G and p are as defined above, can be prepared by reacting a compound of formula (XIV):

(CHR2) (CH2) 2-X

(XIV)

wherein R1, R2, G and p are as defined for formula (I) and X is a leaving group, with a compound of formula (V):

(V) R4

N 25 R3

wherein R3 and R4 are as previously defined herein. For typical reaction conditions, when X is chlorine see Example 35 or alternatively Examples 41-52.

A compound of the formula (XIV), in which R1, G and p are as defined for the formula (I), X is a leaving group and R2 is H (hydrogen) can be prepared by alkylation of a compound of the formula

(XIII) in the presence of a suitable base such as a tertiary amine, for example diisopropylethylamine, with a propyl derivative bearing two leaving groups preferably of differentiated reactivity at positions 1 and 3, for example 1-bromo-3-chloropropane. Typical reaction conditions for this transformation are given in Preparation 40.

Interconversion reactions between compounds of formula (I) and their salts can be performed using methods well known in the art. Examples include:

(i)

 convert one or more R 1 of alkoxy (eg methoxy) into hydroxy,

(ii)

 converting one or more R 1 from hydroxy to sulfonyloxy, such as alkylsulfonyloxy or haloalkylsulfonyloxy, for example methanesulfonyloxy or alkylsulfonyloxy or trifluoromethanesulfonyloxy,

(iii) convert one or more R 1 of halogen or perfluoroalkylsulfonyloxy into cyano;

and optionally after this forming a salt of formula (I).

It has been found that the compounds of formula (I) have affinity towards dopamine receptors, in particular the D3 receptor and can be expected to be useful in the treatment of pathological conditions that require modulation of said receptors, such as in psychotic conditions.

Such affinity is usually calculated from the IC50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand of the receptor and is presented as a value of "Ki". calculated by the following equation:

IC50

Ki �

1� L / KD

in which L = radioligand and KD = radioligand affinity for the receptor (Cheng and Prusoff, Biochem. Pharmacol. 22: 3,099, 1973).

In the context of the present invention pKi (corresponding to the Ki antilogarithm) is used instead of Ki and the compounds of the present invention generally show a pKi greater than 7. In one aspect, the present invention provides compounds of formula ( I) having a pKi between 7 and 8. In another aspect, the present invention provides compounds of formula (I) that have a pKi between 8 and 9. In a further aspect, the present invention provides compounds of formula (I ) that have a pKi greater than 9.

It has also been found that many of the compounds of formula (I) have a greater affinity towards D3 dopamine receptors than towards D2 receptors. It is believed that, in general, the therapeutic effect of currently available antipsychotic agents (neuroleptics) is exerted by blocking D2 receptors; however, it is also believed that this mechanism is responsible for the undesirable extrapyramidal side effects ("eps") associated with many neuroleptic agents. It has been suggested that recently characterized dopamine D3 receptor blockade may produce beneficial antipsychotic activity without significant episodes (see, for example, Sokoloff et al., Nature, 1990; 347: 146-151 and Schwartz et al., Clinical Neuropharmacology, Vol. 16, No. 4, 295-314, 1993). In one embodiment, compounds of the present invention are provided which have greater (eg, 10x or

100x higher) affinity towards dopamine D3 receptors than dopamine D2 receptors (such affinity can be measured using standard methodology, for example, using cloned dopamine receptors - see here). Such compounds may conveniently be used as selective modulators of D3 receptors.

Due to the location of D3 receptors, it can also be envisioned that the compounds could also be useful for the treatment of substance abuse, in which it has been suggested that D3 receptors are involved (eg see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of such substance abuse include alcohol, cocaine, heroin and nicotine abuse. Other conditions that can be treated with the compounds include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, cognitive impairment including memory disorders such as Alzheimer's disease, eating disorders, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, disorders of circadian rhythm, and disorders of gastric motility, for example IBS.

The compounds of formula (I) can be used for the treatment of all aspects of drug dependence, including withdrawal symptoms of drugs such as alcohol, cocaine, opiates, nicotine, benzodiazepines and inhibition of opioid-induced tolerance. In addition, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can be used to reduce the craving for drug use and will therefore be useful in the treatment of craving for drug use. The desire to use drugs can be defined as the motivation of the stimulus to administer a psychoactive substance that had already been consumed previously. Three major factors are involved in the development and maintenance of the craving for drug use: (1) Dysphoric states during drug withdrawal can function as a negative enhancer that leads to the craving for drug use; (2) The environmental stimuli associated with the effects of drugs can become progressively more potent (sensitization) to control the search or craving for drug use and (3) A cognition (memory) of the ability of drugs to favor pleasant effects and relieve a dysphoric state during withdrawal. The craving for drug use may explain the difficulty that people have in abandoning drugs and, therefore, contribute significantly to the development and maintenance of drug dependence.

The compounds of formula (I) are of potential use as antipsychotic agents, for example, in the treatment of schizophrenia, schizoaffective disorders, psychotic depression, mania, paranoid and delusional disorders. In addition, they may be useful as an auxiliary therapy in Parkinson's disease, in particular with compounds such as L-DOPA and possibly dopamine agonists, to reduce the side effects experienced with these treatments in long-term use (for example, see Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242).

In the context of the present invention, the terms describing the indications used herein are classified in the "Diagnostic and Statistical Manual of Mental Disorders" 4th Edition, published by the American Psychiatric Association (DSM-IV) and / or in the International Classification of Diseases, 10th Edition (ICD-10). Various subtypes of disorders mentioned herein are contemplated as part of the present invention. The numbers in parentheses after the diseases listed below, refer to the classification code in DSM-IV.

In the context of the present invention, the terminology "psychotic disorder" includes:

Schizophrenia including the subtypes of Paranoid Type (295.30), Disorganized Type (295.10), Catatonic Type (295.20), Non-Differentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70), which includes the subtypes of Bipolar Type and Depressive Type; delusional disorder (297.1) that includes subtypes of the erotomanic type, delusional type of grandeur, celotypy, persecutory type, somatic type, mixed type and type not otherwise specified; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder due to a generalized medical condition that includes subtypes with delusions and hallucinations; substance-induced psychotic disorder, which includes subtypes with delusions (293.81) and hallucinations (293.82); and Psychotic Disorder Not Specified Otherwise (298.9).

In the context of the present invention, the term "substance related disorder" includes:

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Consumption Craving and Substance Abuse; substance-induced disorders, such as substance intoxication, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced anxiety, substance-induced sexual dysfunction, substance-induced sleep disorder and persistent hallucinogenic perception disorder (flashbacks); alcohol-related disorders such as alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), alcohol withdrawal (291.81), alcohol intoxication delirium, alcohol withdrawal delirium, persistent dementia Alcohol-induced, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and unspecified another way related to alcohol (291.9); disorders related to amphetamines (or amphetamine-like substances) such as amphetamine dependence (304.40), amphetamine addiction (305.70), amphetamine poisoning (292.89), amphetamine withdrawal (292.0), amphetamine poisoning delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and unspecified amphetamine-related disorder (292.9); caffeine-related disorders such as caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorder (292.9); marijuana-related disorders, such as marijuana dependence (304.30), marijuana abuse (305.20), marijuana poisoning (292.89), marijuana intoxication delirium, marijuana-induced psychotic disorder, marijuana-induced anxiety disorder and Marijuana-related disorder not otherwise specified (292.9); Cocaine-Related Disorders, such as the Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Poisoning (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine Induced Psychotic Disorder, Cocaine Induced Emotional State Disorder, Cocaine Induced Anxiety Disorder, Cocaine Induced Sexual Dysfunction, Cocaine Induced Sleep Disorder, and Cocaine Related Disorder Not Specified Otherwise (292.9); Hallucinogen Related Disorders, such as Hallucinogen Dependency (304.50), Hallucinogen Addiction (305.30), Hallucinogen Poisoning (292.89), Hallucinogenic Disorder with Persistent Perception (Retrospective Scenes) (292.89), Intoxication Trauma, Intoxication Hallucinogen Induced Psychotic, Hallucinogen Induced Emotional State Disorder, Hallucinogen Consumption Induced Anxiety Disorder, and Hallucinogen Related Disorder Not otherwise specified (292.9); Inhaler-Related Disorders such as Inhalers Unit (304.60), Inhalers Abuse (305.90), Inhalers Intoxication (292.89), Inhalers Intoxication Delirium, Inhalers-Induced Persistent Dementia, Inhalers-Induced Psychotic Disorder, Emotional State Disorder Inhalers-Induced, Inhalers-Induced Anxiety Disorder and Inhalers-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Specified Otherwise (292.9); Opioid-related disorders, such as opioid dependence (304.00), opioid abuse (305.50), opioid poisoning (292.89), opioid withdrawal (292.0), opioid intoxication delirium, opioid-induced psychotic disorder, opioid disorder opioid-induced mood, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not otherwise specified (292.9); disorders related to phencyclidine (or phencyclidine analogues) such as dependence on phencyclidine (304.60), abuse of phencyclidine (305.90), poisoning with phencyclidine (292.89), delirium from poisoning with phencyclidine, psychotic disorder induced by phencyclidine disorder, mood induced by phencyclidine, anxiety disorder induced by phencyclidine and disorder related to phencyclidine not otherwise specified (292.9); sedative, hypnotic or anxiolytic related disorders, such as sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic abuse (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative, hypnotic withdrawal or anxiolytic (292.0), delirium from sedative, hypnotic or anxiolytic intoxication, delirium from sedative, hypnotic or anxiolytic withdrawal, persistent dementia from sedatives, hypnotics

or anxiolytic, persistent sedative, hypnotic or anxiolytic amnesic disorder, sedative, hypnotic or anxiolytic induced psychotic disorder, sedative, hypnotic or anxiolytic induced emotional state disorder, sedative-induced anxiety disorder, hypnotic or anxiolytic, sexual dysfunction induced by sedatives, hypnotics or anxiolytics, sedative-induced sleep disorder, hypnotics

or anxiolytics and sedative, hypnotic or anxiolytic-related disorder not otherwise specified (292.9); disorder related to several substances such as dependence on several substances (304.80); and other disorders related to substances (or unknown) such as anabolic steroids, nitrate inhalers and nitrous oxide.

The invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment in a mammal of a condition for which modulation (especially antagonism / inhibition) is beneficial. of dopamine receptors (especially D3 dopamine receptors).

The invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment in a mammal of a condition for which modulation (especially antagonism / inhibition) of dopamine receptors (especially of dopamine D3 receptors).

In one embodiment, D3 antagonists according to the present invention are used in the treatment of psychoses such as schizophrenia or in the treatment of substance abuse.

The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a psychotic condition (eg schizophrenia) or substance abuse in a mammal is also provided.

A compound of the formula (I) or a pharmaceutically acceptable salt thereof is also provided for use in the treatment of a psychotic condition (eg schizophrenia) or substance abuse in a mammal.

A compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, for use as an active therapeutic substance in a mammal, eg, for use in the treatment of any of the conditions described herein.

The "treatment" includes prophylaxis, when appropriate for the relevant condition (s).

For use in medicine, the compounds of the present invention are usually administered in the form of a conventional pharmaceutical composition. Therefore, the present invention provides in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically (physiologically) acceptable salt thereof and a pharmaceutically (physiologically) acceptable vehicle. The pharmaceutical composition can be used in the treatment of any of the conditions described herein.

The compounds of formula (I) may be administered by any convenient method, for example, by oral, parenteral (eg, intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions should be adapted accordingly. .

The compounds of formula (I) and their pharmaceutically acceptable salts that are active when administered orally, can be formulated in the form of liquids or solids, for example, syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or a pharmaceutically acceptable salt in a suitable liquid vehicle or vehicles, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending, preservative, flavoring or coloring agent.

A tablet-shaped composition can be prepared using any pharmaceutically acceptable carrier or vehicles, commonly used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using the usual encapsulation procedures. For example, granules containing the active ingredient can be prepared using standard carriers and then loaded into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical vehicle or vehicles, for example, aqueous gums, celluloses, silicates or oils and then loading the dispersion or suspension into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or a pharmaceutically acceptable salt in a sterile aqueous vehicle or in parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or a fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually presented in amounts of a single dose or multiple doses in sterile form in a sealed container, which may have shape of a cartridge or refill for use with an atomization device. Alternatively, the sealed package may be a unit dispensing device such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve that is intended to be discarded once the contents of the package have been finished. When the dosage form comprises an aerosol dispenser, it will contain a propellant that can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also be in the form of a pump atomizer.

Compositions suitable for oral or sublingual administration include tablets, dragees and tablets, in which the active ingredient is formulated with a vehicle such as sugar and gum arabic, tragacanth or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment, the composition is in the form of a unit dose such as a tablet, capsule or blister.

Each dosage unit for oral administration contains, for example, 1 to 250 mg (and for parenteral administration it contains, for example, 0.1 to 25 mg) of a compound of formula (I) or a pharmaceutically acceptable salt. thereof, calculated as the free base.

Pharmaceutically acceptable compounds of the invention will normally be administered in a

5 daily dosing regimen (for an adult patient) of, for example, an oral dose between 1 mg and 500 mg, for example, between 10 mg and 400 mg, p. eg, between 10 and 250 mg or an intravenous, subcutaneous or intramuscular dose between 0.1 mg and 100 mg, for example, between 0.1 mg and 50 mg, e.g. eg, between 1 and 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as a free base, the compound being administered 1 to 4 times a day. Suitably, the compounds will be administered

10 during a period of continuous therapy, for example for a week or more.

Biological Test Methods

The functional potency and intrinsic activity of the compounds of this invention can be measured by following the following GTPyS scintillation proximity test (GTPyS-SPA). The cells used in the study are Chinese Hamster Ovary Cells (CHO).

Cellphone line

CHO_D2

CHO_D3

Cell membranes are prepared as follows. The cell pellets are resuspended in 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the same day, the following proteases are added to the buffer just before administering the homogenization buffer.

20 Leupeptin 10-6 M (Sigma L2884) - stock solution x 5,000 = 5 mg / ml in buffer

Bacitracin 25 ug / ml (Sigma B0125) - stock solution x 1,000 = 25 mg / ml in buffer

1 mM PMSF - stock solution x 1,000 = 17 mg / ml in 100% ethanol

Pepstain A 2x10-6M - stock solution x 1,000 = 2 mM in 100% DMSO

The cells are homogenized by 2 bursts every 15 seconds in a Glass Waring mixer

25 1 liter in a class two biohazard showcase. The resulting suspension is centrifuged at 500 g for 20 min (Beckman T21 centrifuge: 162 rad / s (1,550 rpm)). The supernatant is removed with a 25 ml pipette, poured into aliquots in previously cooled centrifuge tubes and centrifuged at 48,000 g to settle the membrane fragments (Beckman T1270: 2,408 rad / s (23,000 rpm) for 30 min ). The final sediment of 48,000 g is resuspended in the Homogenization Buffer (4 x the

30 volume of the original cell pellet). The 48,000 g sediment is resuspended by vortexing for 5 seconds and homogenized in a 10-15 beat homogenizer. The preparation is distributed in aliquots of the appropriate size, (200-1,000 ul), in polypropylene tubes and stored at -800 C. The protein content of the membrane preparations is evaluated with the Bradford protein assay.

35 In the assay, the final highest concentration of test drug is 3 µM and dilution curves are performed

1: 4 in series of 11 points in 100% DMSO using a Biomek FX. The test drug in a total test volume (TAV) of 1% is added to a solid, white 384 well test plate. 50% of the TAV of pre-coupled membranes (for 90 minutes at 4 ° C), 5 µg / well and Twinkling Beads by Proximity of Polystyrene with Wheat Germ Agglutinin (RPNQ0260, Amersham), 0.25 mg / well, 40 in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 60 µg / ml saponin and 30 M GDP. The third addition was a 20% addition of the TAV buffer (agonist format) or a concentration of EC80 final trial of agonist, Quinelorano, prepared in the assay buffer (antagonist format). Essay

It began by adding 29% of the TAV of GTPy [35S] 0.38 nM final (37 MBq / ml, 1,160 Ci / mmol, Amersham). After all additions, the test plates are centrifuged for 1 minute at 105 to 45 rad / s (1,000 rpm). The test plates are counted on a Viewlux 613/55 filter, for 5 min, between 2-6 hours after the final addition.

The effect of the test drug on the initial situation generates the EC50 value with an adjustment program

iterative of minimum-quadratic curves, which is expressed in the table as pCE50 (that is, -log CE50). The relationship between the maximum effect of the test drug and the maximum effect of the total agonist, Quinelorano, generates the value of Intrinsic Activity (AI) (that is, AI = 1 total agonist, AI <1 partial agonist). The fpKi values of the test drug are calculated from the IC generated by the "format" experiment.

antagonist ”, using the equation Cheng &amp; Prusoff: fKi = IC50 / 1 + ([A] / EC50) in which: [A] is the concentration 5 of the 5-HT agonist in the test and EC50 is the 5-HT value EC50 obtained in the same experiment. fpKi is defined as -logfKi.

The compounds of the invention listed above have pKi values in the range 7.0-10.5 in the dopamine D3 receptor. The results of pKi are estimated to be accurate only at around ± 0.3-0.5.

The compounds of the invention listed above have a selectivity on D2 greater than 30.

Examples

The present invention is further illustrated by the following Examples. Preparations 1 to 5 were performed analogously to the synthetic route described in J.Med.Chem. 1981, 24, 481-490.

All temperatures are expressed in ° C. The infrared spectra were measured on an FT-IR instrument.

The compounds were analyzed by direct infusion of the sample dissolved in acetonitrile into mass spectra operated in positive ionization mode by electroatomization (ES +). Proton Magnetic Resonance (1H NMR) spectra were recorded at 400 MHz, chemical shifts are reported in ppm at low field (d) from Me4Si, used as internal standard, and are assigned as singles (s), wide singles ( bs), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiples (m).

The experimental vibrational circular dichroism (VCD) spectra were measured using a ChiraIIRTM VCD spectrometer operating in the 2,000-800 cm-1 frequency range. Spectra were measured at room temperature (23 ° C) using a sealed transmission cell with barium fluoride slots and a path length of 100 microns. (Scanning times varied from 60 to 120 minutes per isomer.) Sample solutions were usually prepared

25 by dissolving 10 milligrams of each enantiomer in 100 microliters of deutero-chloroform (CDCI3). For ab initio assignments, non-polarized VCD and IR spectra were calculated using the Gaussian 98 v.1 software package.

Optical rotations were measured using a polarimeter (Perkin Elmer Model 241) operating at 589 nm (source of Sodium). Measurements were made using a thermostated 1 decimeter microcell at 23 ° C. The concentrations were usually 10 mg / ml (c = 0.01). For initial OR assignments, the Dalton Quantum Chemistry Program was used.

Column chromatography was performed on silica gel (Merck AG Darmstaadt, Germany). In the text, the following abbreviations are used: NBS = N-bromosuccinimide, Vitride = &quot; Red-AI® &quot;, HOBt = 1hydroxybenzotriazole EtOAc = ethyl acetate, Et2O = diethyl ether, DMF = N, N'-dimethylformamide, MeOH =

35 methanol, TFA = trifluoroacetic acid, tetrahydrofuran = tetrahydrofuran, IPA = isopropanol, TEA = triethylamine, DCC = 1,3-dicyclohexylcarbodiimide, SCX = intense cation exchanger, Tlc refers to thin layer chromatography on silica plates, and dry refers to a dried solution over anhydrous sodium sulfate, ta (TA) refers to room temperature, Tr = retention time, DMSO = dimethyl sulfoxide.

Preparation 13: 5- {5 - [(3-Chloropropyl) thio] -4-methyl-4H-1,2,4-triazol-3-yl} -2-methylquinoline

A 4-methyl-5- (2-methyl-5-quinolinyl) -2,4-dihydro-3H-1,2,4-triazol-3-thione (3.6 g, prepared analogously to the procedure to be described in WO200240471) in ethanol (60 ml) containing 1-bromo-3-chloropropane (2.0 ml) stirring sodium hydride (0.60 g, 60% in petroleum) was added with caution. The

The mixture was heated at reflux for 45 min. The volatile matter was evaporated in vacuo and the residue was subjected to column chromatography (EtOAc-acetone gradient). The material thus obtained was precipitated from hot EtOAc (20 ml) by adding petroleum ether (40-60, 50 ml), cooled and collected by filtration to give the title compound as colorless crystals (2.1 g ).

NMR (1H, CDCl3): 8 8.18 (d, 1H), 8.12 (d, 1H), 7.76 (t, 1H), 7.55 (d, 1H), 7.30 (d, 1H), 3.75 (t, 2H), 3.50 (t, 2H), 3.40 (s, 3H), 2.76 (s, 3H), 2.37 (m, 2H).

A mixture of hydrochloric acid (37%, 285 ml) and water (190 ml) was added to 4- (trifluoromethyl) aniline (150 g, 116 ml) at room temperature with vigorous stirring and the precipitate formed was left stirring during stirring. 30 more minutes. The temperature was reduced to 0 ° C and sodium nitrite (70.6 g) in 180 ml of water was added dropwise to the stirred suspension. At the end of the diazotation, a light yellow solution was obtained. Maleimide (180 g) in acetone (1.1 L) was added dropwise at 0 ° C and then the pH of the solution was adjusted to 3-3.5 by the addition of sodium acetate. To the vigorously stirred mixture was added copper (II) chloride (18.8 g). After a few minutes, a gas began to come off (foaming

10 visible). The reaction mixture was allowed to stir at 0 ° C for 1 h and overnight at room temperature.

The acetone was removed in vacuo, the residue was filtered and dried overnight in vacuo to give the title compound (155 g) as a light brown solid (y = 63%).

MS (m / z): 242.2 [MH] +. Preparation 16: (1R, 5S / 1S, 5R) -1- [4- (Trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] -hexane-2,4-dione

Ground sodium hydroxide (40 g) was added in small portions to a stirred solution of trimethylsulfoxonium iodide (219 g) in DMSO (anhydrous, 2 L). The resulting mixture was left under stirring at room temperature for 1.5 h.

Then 3- [4- (trifluoromethyl) phenyl] -1 H -pyrrol-2,5-dione (Preparation 15, 120 g) dissolved in DMSO (anhydrous, 0.5 L) was added dropwise and the resulting mixture was Let stir at room temperature for 20 minutes. The temperature was then reduced to 0 ° C and NH4Cl (saturated aqueous solution, 2 L) was added slowly, followed by Et2O (1 L). After separation of the two phases, the aqueous layer was repeatedly extracted with Et2O (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L) and then dried

25 over Na2SO4. Evaporation of the solvent gave a light brown solid that was suspended in 1 L of dichloromethane and 1 L of cyclohexane. The mixture was allowed to stir at room temperature for 45 minutes and then filtered to provide the title compound (116 g) as a white solid (yield = 71%).

MS (m / z): 256.1 [MH] +. Preparation 17: (1R, 5S / 1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane

Borane (1 M in tetrahydrofuran, 1.4 L) was charged in a 5 L reactor in an N2 atmosphere and cooled to 0 ° C. Then (1R, 5S / 1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane-2,4-dione (Preparation

16, 101 g) dissolved in tetrahydrofuran (anhydrous, 1 L) with vigorous stirring so that the temperature was kept constantly below 5 ° C, and the evolution of gas was monitored. At the end of the addition, the resulting mixture was left under stirring at 0 ° C for 1 h and then at room temperature overnight.

The mixture was then allowed to cool to 0 ° C and methanol (200 ml) was carefully added followed by hydrochloric acid (6 M solution, 0.8 L) monitoring the evolution of gas. The tetrahydrofuran was then removed in vacuo, the residue was cooled to 0 ° C and sodium hydroxide (5 M solution) was added until pH 9-10 was reached. The aqueous layer was extracted with Et2O (3 x 1 L). Removal of the solvent in vacuo provided the title compound (140 g) as a colorless oil.

10 MS (m / z): 228.1 [MH] +. Preparation 18: (1S, 5R) -1- [4- (Trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane

(S) - (+) - Mandelic acid (94 g) was added portionwise to a stirred solution of (1R, 5S / 1S, 5R) -1- [4

(trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (Preparation 17, 140 g) in 1.4 L of tetrahydrofuran. Mix

The resultant was stirred at room temperature for 2 h until a white precipitate formed. Then, the mixture was heated to reflux temperature, stirred for 45 minutes and then slowly cooled to room temperature. The white solid was collected by filtration and dried in vacuo. This material was recrystallized 4 times in tetrahydrofuran (10 volumes) to provide 32.5 g of a white solid.

Then, this material was suspended in sodium hydroxide (1M solution, 400 mL) and Et2O (400 mL) and was

20 left stirring at room temperature until the solution was complete. After separation of the two phases, the aqueous layer was extracted again with Et2O (3 x 250 mL). The combined organic layers were washed with sodium hydroxide (1 M solution, 3 x 200 ml) and then dried over Na2SO4. Evaporation of the solvent in vacuo provided the title compound (19 g) as a white solid (yield = 37%).

The absolute configuration of the optical isomers was assigned through the use of comparative VCD analysis (vibrational circular dichroism) and OR (optical rotation).

The title compound configuration was assigned by comparing its experimental VCD spectrum and the specific rotation observed with the data observed for (1S, 5R) -1- (3,4-dichlorophenyl) -3azabicyclo [3.1.0] hexane (see Preparation 48) as reference sample.

The assignment of the absolute configuration of the title compound was confirmed by a single crystal X-ray structure obtained from a crystal of (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1 .0] hexane, acid salt (S) - (+) - mandelic. Both the analysis based on the known configuration of the (S) (+) mandelic acid and the one based on the anomalous dispersion effects confirmed the assignment of the title compound as (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane.

NMR (1H, CDCl3): 8 7.51 (d, 2H), 7.25 (d, 2H), 3.20 (d, 1H), 3.0-3.1 (m, 3H), 1 , 69 (m, 1H), 0.8-1.0 (m, 2H), NH not observed. MS (m / z): 228.1 [MH] +.

Analytical chromatography

Column: chiralcel OD 10 µm, 250 x 4.6 mm Mobile phase: A: n-hexane; B: Isopropanol + 0.1% Isopropylamine

40 Gradient: 2% isocratic B Flow rate: 1 mL / min UV wavelength range: 200-400 nm Analysis duration 25 min ret time. (min)% y / y

45 16.5 0.4 (1R, 5S) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane 21.7 99.6 title compound Specific Optical Rotation: [a] D = -10 ° (CDCl3, T = 20 ° C, 0.004 g / 0.8 ml).

Preparation 21: 1- {5 - [(1S, 5R / 1R, 5S) -3-Azabicyclo [3.1.0] hex-1-yl) -2- (methyloxy) phenyl} ethanone

The title compound was prepared in 32 mg yield from 1- [4- (methyloxy) phenyl] -3 (trifluoroacetyl) -3-azabicyclo [3.1.0] hexane (94 mg) as described for the preparation 3. 4.

MS (m / z): 232 [MH] +. HPLC: condition 1, Rt = 3.393 min. Preparation 40: (1S, 5R) -3- (3-Chloropropyl) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane

F

To a solution of (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (1.00 g) in dry tetrahydrofuran (5 ml), diisopropylethylamine (2 , 4 ml) and 1-bromo-3-chloropropane (3.7 ml) and the

10 resulting mixture at reflux for 3 hours. After cooling to room temperature, it was diluted with ethyl acetate (30 ml), washed twice with a saturated solution of NH4Cl in water (20 ml) and once with a saturated solution of NaHCO3 in water (20 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 7: 3 cyclohexane / EtOAc to give the title compound as a colorless oil (1.26 g).

15 NMR (1H, CDCl3): 8 7.50 (d, 2H) 7.19 (d, 2H), 3.59 (t, 2H), 3.33 (d, 1H), 3.09 (d, 1H), 2.58 (m, 2H), 2.66 (dd, 1H), 2.46 (dd, 1H), 1.92 (m, 2H), 1.74 (m, 1H), 1, 67 (t, 1H), 0.81 (dd, 1H). MS (m / z): 304 [MH +].

Examples 41-52:

To a solution of the respective 3-thio-5-aryl-1,2,4-triazole (prepared by analogy with the method described in the

Preparation 13, 0.131 mmol) in dry acetonitrile (2 mL) was added 2-tert-butylimino-2-diethylamino-1,3-dimethyl-20 perhydro-1,3,2-diaza-phosphorin over polystyrene (90 mg, 2.2 mmol / g) and the resulting mixture was shaken

for 30 minutes at room temperature. Then, (1S, 5R) -3- (3-chloropropyl) -1- [4

(trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (40 mg) and the resulting mixture was shaken at 70 ° C for three

hours. After cooling, the resin was filtered off, washed with methanol (2 ml) and then removed

the solvent under reduced pressure. Purifications were performed using mass directed HPLC using a 10 µm Waters XTerra Prep MS C18 column, 30 x 150 mm, using the following conditions:

Weather

Flow % TO % B

Pre-elution

0 40 ml / min 99 one

one

40 ml / min 99

one

Elution

0 40 ml / min 99 one

10

40 ml / min 75 25

14.5

40 ml / min 10 90

fifteen

40 ml / min 0 100

Post-reflection

0 40 ml / min 0 100

0.2

45 ml / min 0 100

1.5

45 ml / min 0 100

2

40 ml / min 0 100

A = H2O + 0.1% formic acid

B = ACN + 0.1% formic acid

The solvent was then removed under reduced pressure, to provide the respective title compounds as formate salts. The residues were collected with methanol (1 mL) and loaded onto cartridges

SCX SPE (1g), which were washed with methanol (3 mL) and eluted with a 2M solution of ammonia in methanol (3 mL), and then the solvent was removed under reduced pressure. The residues were collected with dichloromethane (1 mL) and a solution of 1.0 M HCl in diethyl ether (0.131 mmol) was added, then the solvent was removed under reduced pressure to give the product compounds summarized in TABLE 1 as hydrochloride salts .

5 Analytical chromatographic conditions:

Column: X Terra MS C18 5 µm, 50 x 4.6 mm Mobile phase: A: dissol. 10 mM NH4HCO3, pH 10; B: CH3CN Gradient: 10% (B) for 1 min, from 10% (B) to 95% (B) in 12 min, 95% (B) for 3 min Flow: 1 mL / min

10 UV wavelength range: 210-350 nm Mass range: 100-900 uma

Ionization: ES +

TABLE 1

Ex.

Denomination and structure R (min) Analytical data

42

(1S, 5R) -3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4 (trifluoromethyl) phenyl hydrochloride ] -3azabicyclo [3.1.0] hexane NNNN NS NF FF H ClH 8.84 NMR (1H, DMSO): 8 10.24 (bs, HCl), 9.56 (m, 1H), 9.39 (m, 1H), 8.01 (s, 1H), 7.64 (m, 2H), 7.44 (m, 2H), 4.08 (m, 1H), 3.68 (s, 3H), 3.58 (bm, 1H), 3.7-3.3 (m, 6H ), 2.26 (m, 1H), 2.13 (m, 2H), 1.58 (t, 1H), 1.14 (t, 1H). MS (m / z): 461 [MH] +.

Claims (12)

1.3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4- (trifluoromethyl) phenyl] -3 -azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, which corresponds to a compound of formula (I): N N N (CHR2) (CH2) 2 S (I) N R4 (R1) p R3 5 in which

•

G is phenyl and (R1) p is 4-trifluoromethyl;

•

R2 is hydrogen;

•

R3 is methyl;

•

R4 is 4-pyridazinyl

2. A compound of formula (IB) or a pharmaceutically acceptable salt thereof wherein R1, p, R3 and R4 are defined as in claim 1. N N N (CH2) 3 S (IB) N R4 (R1) p R3 3. A stereochemical isomer enriched in the configuration (1S, 5R) of the formula (IB) 'or a salt pharmaceutically acceptable thereof, wherein R1, p, R3 and R4 are as defined in claim 1. N N N (CH2) 3 S H (IB) 'N R4 (R1) p R3 4. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1-3 that is selected from a group consisting of: (1S, 5R) -3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) -1- [4- ( trifluoromethyl) phenyl] -320 azabicyclo [3.1.0] hexane; (1S, 5R) -3- (3 - {[4-Methyl-5- (4-pyridazinyl) -4H-1,2,4-triazol-3-yl] thio} propyl) hydrochloride -1- [4 - (trifluoromethyl) phenyl] -3azabicyclo [3.1.0] hexane; 5. A process for preparing a compound according to claim 1, the process comprising the steps of: Reacting a compound of formula (XIV): (CHR2) (CH2) 2-X (XIV) wherein R1, R2, G and p are as defined for formula (I) and X is a leaving group, with a compound of formula (V): (V) R4 N R3 wherein R3 and R4 are as defined in claim 1. 6. (1S, 5R) -3- (3-Chloropropyl) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane, as intermediate in the preparation of the compound of formula (I) according to claim 5. 7. 4-Methyl-5- (4-pyridazinyl) -2,4-dihydro-3H-1,2,4-triazol-3-thione, as intermediate in HS the preparation of the compound of formula (I) according to claim 5. 8. Use of a compound according to any of claims 1-4 in the manufacture of a medicament for the treatment of psychosis or a psychotic condition or substance abuse. 9. Use of a compound according to any one of claims 1-4 in the manufacture of a medicament for the treatment of substance abuse.

10.

 Use according to claim 8, wherein the psychotic condition is schizophrenia.

eleven.

 A compound according to any of claims 1-4 for use in therapy.

12.

 A compound according to any of claims 1-4, for use in the treatment of psychosis or a psychotic condition, or for the treatment of substance abuse.

A compound according to any one of claims 1-4, for use in the treatment of schizophrenia. 14. A pharmaceutical composition comprising a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier.